{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T17:10:48Z","timestamp":1769620248206,"version":"3.49.0"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Karlheinz-Hartmann-Stiftung, Hannover, Germany","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>In multiple system atrophy (MSA), the fatal movement disorder, cell populations of the striatum and other subcortical brain regions degenerate, leading to a rapidly progressive, atypical Parkinsonian syndrome. The pathophysiology of neurons and glial cells shows misfolding, aggregation, and increased release of the protein \u03b1-synuclein. In addition, neuronal hypoexcitability, a reduction in the activity of the mitochondrial respiratory chain, and a dysregulation of the enzymes involved in the biosynthesis of coenzyme Q10 were observed in human stem-cell models. In this study, untargeted and targeted metabolome analyses were performed with MSA patient-derived GABAergic striatal medium spiny neurons focusing on the citrate cycle and mitochondrial respiratory chain. The results indicate a significant decrease in succinate and ATP as well as an imbalanced NAD+\/NADH ratio of MSA cell lines compared to matched healthy controls, suggesting alterations in mitochondrial processes which may facilitate neurodegeneration.<\/jats:p>","DOI":"10.3390\/biom16020190","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T15:48:30Z","timestamp":1769442510000},"page":"190","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolomics of Multiple System Atrophy Patient-Derived Striatal Medium Spiny Neurons"],"prefix":"10.3390","volume":"16","author":[{"given":"Nadine J.","family":"Smandzich","sequence":"first","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"},{"name":"Center for Systems Neuroscience Hannover (ZSN), 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike","family":"B\u00e4hre","sequence":"additional","affiliation":[{"name":"Core Unit Metabolomics, Institute of Pharmacology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Gschwendtberger","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Greten","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3054-9905","authenticated-orcid":false,"given":"Martin","family":"Klietz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6478-026X","authenticated-orcid":false,"given":"Alessio","family":"Di Fonzo","sequence":"additional","affiliation":[{"name":"Neurology Unit, IRCCS Foundation Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa M.","family":"Henkel","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Wegner","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hannover Medical School, 30625 Hannover, Germany"},{"name":"Center for Systems Neuroscience Hannover (ZSN), 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.3233\/JAD-170397","article-title":"Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy","volume":"62","author":"Jellinger","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1007\/s00415-024-12269-5","article-title":"Multiple System Atrophy: An Update and Emerging Directions of Biomarkers and Clinical Trials","volume":"271","author":"Liu","year":"2024","journal-title":"J. Neurol."},{"key":"ref_3","first-page":"100271","article-title":"Multiple System Atrophy: Diagnostic Challenges and a Proposed Diagnostic Algorithm","volume":"11","author":"Nandanwar","year":"2024","journal-title":"Clin. Park. Relat. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41572-022-00382-6","article-title":"Multiple System Atrophy","volume":"8","author":"Poewe","year":"2022","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1002\/mds.29005","article-title":"The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy","volume":"37","author":"Wenning","year":"2022","journal-title":"Mov. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41531-021-00264-w","article-title":"Similar Neuronal Imprint and No Cross-Seeded Fibrils in \u03b1-Synuclein Aggregates from MSA and Parkinson\u2019s Disease","volume":"8","author":"Claverol","year":"2022","journal-title":"npj Park. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Henkel, L.M., Kankowski, S., Moellenkamp, T.M., Smandzich, N.J., Schwarz, S., Di Fonzo, A., G\u00f6hring, G., H\u00f6glinger, G., and Wegner, F. (2023). IPSC-Derived Striatal Medium Spiny Neurons from Patients with Multiple System Atrophy Show Hypoexcitability and Elevated \u03b1-Synuclein Release. Cells, 12.","DOI":"10.3390\/cells12020223"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/nature05292","article-title":"Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases","volume":"443","author":"Lin","year":"2006","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1515\/revneuro-2024-0080","article-title":"Unraveling Mitochondrial Dysfunction: Comprehensive Perspectives on Its Impact on Neurodegenerative Diseases","volume":"36","year":"2025","journal-title":"Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"102720","DOI":"10.1016\/j.conb.2023.102720","article-title":"Novel Insights into Parkin-Mediated Mitochondrial Dysfunction and Neuroinflammation in Parkinson\u2019s Disease","volume":"80","author":"Pereira","year":"2023","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.freeradbiomed.2016.04.200","article-title":"Energy Metabolism and Inflammation in Brain Aging and Alzheimer\u2019s Disease","volume":"100","author":"Yin","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.parkreldis.2017.10.010","article-title":"Cerebrospinal Fluid Levels of Coenzyme Q10 Are Reduced in Multiple System Atrophy","volume":"46","author":"Compta","year":"2018","journal-title":"Park. Relat. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1016\/j.stemcr.2018.09.007","article-title":"Mitochondrial Dysregulation and Impaired Autophagy in IPSC-Derived Dopaminergic Neurons of Multiple System Atrophy","volume":"11","author":"Kleiner","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40035-023-00370-0","article-title":"Multidimensional Biomarkers for Multiple System Atrophy: An Update and Future Directions","volume":"12","author":"Wan","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"George, N.P., Kwon, M., Jang, Y.E., Kim, S.G., Hwang, J.S., Lee, S.S., and Lee, G. (2025). Integrative Analysis of Metabolome and Proteome in the Cerebrospinal Fluid of Patients with Multiple System Atrophy. Cells, 14.","DOI":"10.3390\/cells14040265"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kwon, D.H., Hwang, J.S., Kim, S.G., Jang, Y.E., Shin, T.H., and Lee, G. (2022). Cerebrospinal Fluid Metabolome in Parkinson\u2019s Disease and Multiple System Atrophy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031879"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mori, A., Ishikawa, K.-I., Saiki, S., Hatano, T., Oji, Y., Okuzumi, A., Fujimaki, M., Koinuma, T., Ueno, S.-I., and Imamichi, Y. (2019). Plasma Metabolite Biomarkers for Multiple System Atrophy and Progressive Supranuclear Palsy. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0223113"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pathan, M., Wu, J., Lakso, H.-\u00c5., Forsgren, L., and \u00d6hman, A. (2021). Plasma Metabolite Markers of Parkinson\u2019s Disease and Atypical Parkinsonism. Metabolites, 11.","DOI":"10.3390\/metabo11120860"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nrm.2016.25","article-title":"Metabolomics: Beyond Biomarkers and towards Mechanisms","volume":"17","author":"Johnson","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1007\/s13361-016-1469-y","article-title":"Untargeted Metabolomics Strategies\u2014Challenges and Emerging Directions","volume":"27","author":"Codreanu","year":"2016","journal-title":"J. Am. Soc. Mass. Spectrom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.nbd.2015.05.004","article-title":"Fluid Biomarkers in Multiple System Atrophy: A Review of the MSA Biomarker Initiative","volume":"80","author":"Laurens","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.neuron.2008.11.005","article-title":"Striatal Plasticity and Basal Ganglia Circuit Function","volume":"60","author":"Kreitzer","year":"2008","journal-title":"Neuron"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Staege, S., Kutschenko, A., Baumann, H., Gla\u00df, H., Henkel, L., Gschwendtberger, T., Kalmbach, N., Klietz, M., Hermann, A., and Lohmann, K. (2021). Reduced Expression of GABAA Receptor Alpha2 Subunit Is Associated with Disinhibition of DYT-THAP1 Dystonia Patient-Derived Striatal Medium Spiny Neurons. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.650586"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Winterhoff, M., Chen, F., Sahini, N., Ebensen, T., Kuhn, M., Kaever, V., B\u00e4hre, H., and Pessler, F. (2021). Establishment, Validation, and Initial Application of a Sensitive LC-MS\/MS Assay for Quantification of the Naturally Occurring Isomers Itaconate, Mesaconate, and Citraconate. Metabolites, 11.","DOI":"10.3390\/metabo11050270"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nprot.2011.319","article-title":"Web-Based Inference of Biological Patterns, Functions and Pathways from Metabolomic Data Using MetaboAnalyst","volume":"6","author":"Xia","year":"2011","journal-title":"Nat. Protoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14.10.1","DOI":"10.1002\/0471250953.bi1410s34","article-title":"Metabolomic Data Processing, Analysis, and Interpretation Using MetaboAnalyst","volume":"34","author":"Xia","year":"2011","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Li, S., Park, Y., Duraisingham, S., Strobel, F.H., Khan, N., Soltow, Q.A., Jones, D.P., and Pulendran, B. (2013). Predicting Network Activity from High Throughput Metabolomics. PLoS Comput. Biol., 9.","DOI":"10.1371\/journal.pcbi.1003123"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7674","DOI":"10.1038\/s41467-023-42862-7","article-title":"A Reversible State of Hypometabolism in a Human Cellular Model of Sporadic Parkinson\u2019s Disease","volume":"14","author":"Schmidt","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Smandzich, N.J., Pich, A., Gschwendtberger, T., Greten, S., Ye, L., Klietz, M., Di Fonzo, A., Henkel, L.M., and Wegner, F. (2025). Proteomics of Patient-Derived Striatal Medium Spiny Neurons in Multiple System Atrophy. Cells, 14.","DOI":"10.3390\/cells14171394"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.1016\/j.celrep.2018.05.009","article-title":"The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in IPSC and Fly Models of Parkinson\u2019s Disease","volume":"23","author":"Ivanyuk","year":"2018","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1016\/j.stemcr.2017.10.010","article-title":"Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S IPSC-Derived Dopaminergic Neurons","volume":"9","author":"Schwab","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e13658","DOI":"10.1111\/acel.13658","article-title":"Nicotinamide Riboside and Caffeine Partially Restore Diminished NAD Availability but Not Altered Energy Metabolism in Alzheimer\u2019s Disease","volume":"21","author":"Ryu","year":"2022","journal-title":"Aging Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/ana.24551","article-title":"Leigh Syndrome: One Disorder, more than 75 Monogenic Causes","volume":"79","author":"Lake","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ishima, T., Kimura, N., Kobayashi, M., Watanabe, C., Jimbo, E.F., Kobayashi, R., Horii, T., Hatada, I., Murayama, K., and Ohtake, A. (2024). NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model. Biomolecules, 15.","DOI":"10.3390\/biom15010038"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41582-018-0101-0","article-title":"POLG-Related Disorders and Their Neurological Manifestations","volume":"15","author":"Rahman","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e12146","DOI":"10.15252\/emmm.202012146","article-title":"Disease-specific Phenotypes in IPSC-derived Neural Stem Cells with POLG Mutations","volume":"12","author":"Liang","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1083\/jcb.201401009","article-title":"Assembly Factors Monitor Sequential Hemylation of Cytochrome b to Regulate Mitochondrial Translation","volume":"205","author":"Hildenbeutel","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mito.2020.04.002","article-title":"Molecular Mechanism of Mitochondrial Respiratory Chain Assembly and Its Relation to Mitochondrial Diseases","volume":"53","author":"Mukherjee","year":"2020","journal-title":"Mitochondrion"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"102838","DOI":"10.1016\/j.jbc.2022.102838","article-title":"Regulation and Function of the Mammalian Tricarboxylic Acid Cycle","volume":"299","author":"Arnold","year":"2023","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101674","DOI":"10.1016\/j.redox.2020.101674","article-title":"Mitochondrial Electron Transport Chain: Oxidative Phosphorylation, Oxidant Production, and Methods of Measurement","volume":"37","author":"Braganza","year":"2020","journal-title":"Redox Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.beem.2012.05.003","article-title":"Cellular and Molecular Mechanisms of Mitochondrial Function","volume":"26","author":"Osellame","year":"2012","journal-title":"Best. Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.bbabio.2016.03.012","article-title":"Succinate, an Intermediate in Metabolism, Signal Transduction, ROS, Hypoxia, and Tumorigenesis","volume":"1857","author":"Tretter","year":"2016","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Bioenerg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1002\/1878-0261.13808","article-title":"Respiratory Complex I-mediated NAD+ Regeneration Regulates Cancer Cell Proliferation through the Transcriptional and Translational Control of P21Cip1 Expression by SIRT3 and SIRT7","volume":"19","author":"Higurashi","year":"2025","journal-title":"Mol. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1016\/j.cmet.2021.06.013","article-title":"Glycerol-3-Phosphate Biosynthesis Regenerates Cytosolic NAD+ to Alleviate Mitochondrial Disease","volume":"33","author":"Liu","year":"2021","journal-title":"Cell Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1146\/annurev-nutr-120420-025558","article-title":"Ins and Outs of the TCA Cycle: The Central Role of Anaplerosis","volume":"41","author":"Inigo","year":"2021","journal-title":"Annu. Rev. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Lancaster, M.S., and Graham, B.H. (2023). Succinyl-CoA Synthetase Dysfunction as a Mechanism of Mitochondrial Encephalomyopathy: More than Just an Oxidative Energy Deficit. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310725"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Salcedo, C., Andersen, J.V., Vinten, K.T., Pinborg, L.H., Waagepetersen, H.S., Freude, K.K., and Aldana, B.I. (2021). Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in IPSC-Derived Astrocytes in Alzheimer\u2019s Disease. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.736580"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"827","DOI":"10.3727\/096368910X540630","article-title":"Neuroprotective Effect of Human Mesenchymal Stem Cells in an Animal Model of Double Toxin-Induced Multiple System Atrophy Parkinsonism","volume":"20","author":"Park","year":"2011","journal-title":"Cell Transpl."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.nbd.2019.03.020","article-title":"A Mouse Model of Adult-Onset Multiple System Atrophy","volume":"127","author":"Tanji","year":"2019","journal-title":"Neurobiol. Dis."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/2\/190\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T05:13:25Z","timestamp":1769577205000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/2\/190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,26]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["biom16020190"],"URL":"https:\/\/doi.org\/10.3390\/biom16020190","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,26]]}}}